Project Summary Of people admitted emergently to the Intensive Care Unit (ICU) in respiratory failure or shock, 50% to 70% develop delirium (by far the highest in any healthcare setting). The duration of this delirium independently predicts earlier death, longer hospital stay, and higher healthcare expenses annually. Delirium in ICU patients has been shown to be the strongest potentially modifiable risk factor for development of a long-term cognitive impairment, which resembles moderate to severe Alzheimer?s Disease and Related Dementias (ADRDs). Thus, medical and surgical ICU patients on ventilators or in shock are a prime population in whom to study the relationship between delirium and dementia. Our NIA-funded, NEJM published, and PAR-18-029 cited BRAIN- ICU-1 study [Bringing to light the Risk factors And Incidence of Neuropsychological dysfunction in ICU Survivors, 1st Study] showed over that one-third of ICU survivors (without preexisting dementia) emerged with new cognitive impairments or ADRD at 1 year. Some BRAIN-ICU-1 patients had cognitive resilience against ADRD, but others developed a persistent or progressive dementia-like illness. We are eager to develop interventions against this ICU-related dementia, but without knowing more about this form of brain injury, we are very limited. Now, we have pilot neuroimaging (MRI) data show that acute ICU delirium is associated with atrophy of the whole brain, frontal lobe, and hippocampus, but this problem requires an in-depth investigation. We know abnormal brain proteins (amyloid, tau) relate to Alzheimer?s disease, however, we know nearly nothing about protein pathology or other causes of this ICU-related dementia. It is critical to understand why ICU survivors are losing their jobs, and the leadership as matriarchs and patriarchs of their families. This BRAIN-ICU-2 study [Bringing to light the Risk factors And Incidence of Neuropsychological dysfunction (dementia) in ICU Survivors, 2nd Study] is in direct response to PAR-18-029 and will determine ICU patients? main paths to decline, maintenance, or recovery of brain function. We will answer gaps in knowledge about long-term outcome of post-ICU brain disease by following the remaining ICU survivors from the original BRAIN-ICU-1 study with complete cognitive testing for the first time ever to 14 years (AIM 1). We will consent and enroll 567 new ICU patients at Vanderbilt and Rush Universities (i.e., new ICU cohort) and determine how detailed neuroimaging and cerebrospinal fluid samples can help reveal locations and mechanisms of injury beyond what we learned from the clinical information collected in our original study (AIM 2). Importantly, we are partnering with the world-renowned Rush Alzheimer's Disease Research Center brain bank program so that all patients enrolled in Aims 1 and 2 will able to donate their brains to science for the first-ever in-depth pathological study of those who do and do not get post-ICU dementia to define this disease formally (AIM 3).